10-70055076-A-G

Variant names:

• chr10-70055076-A-G
• rs4746946
• NM_018649.3:c.-60+2076A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018649.3(MACROH2A2):​c.-60+2076A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,068 control chromosomes in the GnomAD database, including 19,147 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19147 hom., cov: 32)
• Consequence: MACROH2A2 NM_018649.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 1 publications found

Genes affected

MACROH2A2 (HGNC:14453): (macroH2A.2 histone) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a replication-independent histone that is a member of the histone H2A family. It replaces conventional H2A histones in a subset of nucleosomes where it represses transcription and may participate in stable X chromosome inactivation. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018649.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROH2A2	NM_018649.3	MANE Select	c.-60+2076A>G		intron	N/A	NP_061119.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROH2A2	ENST00000373255.9	TSL:1 MANE Select	c.-60+2076A>G		intron	N/A	ENSP00000362352.3
	MACROH2A2	ENST00000679349.1		c.-161A>G		5_prime_UTR	Exon 2 of 10	ENSP00000503835.1
	MACROH2A2	ENST00000676699.1		c.-60+2076A>G		intron	N/A	ENSP00000503741.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75669 AN: 151950 Hom.: 19120 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.498

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75749 AN: 152068 Hom.: 19147 Cov.: 32 AF XY: 0.501 AC XY: 37228 AN XY: 74344

African (AFR) AF: 0.522 AC: 21661 AN: 41478

American (AMR) AF: 0.582 AC: 8899 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1556 AN: 3466

East Asian (EAS) AF: 0.662 AC: 3420 AN: 5170

South Asian (SAS) AF: 0.628 AC: 3028 AN: 4824

European-Finnish (FIN) AF: 0.406 AC: 4284 AN: 10564

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31310 AN: 67966

Other (OTH) AF: 0.498 AC: 1053 AN: 2116

Alfa AF: 0.480 Hom.: 22534

Bravo AF: 0.511

Asia WGS AF: 0.630 AC: 2191 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	19
DANN	Benign	0.63
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4746946; hg19: chr10-71814832;